17-41769098-A-G
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting
The NM_002230.4(JUP):c.578T>C(p.Met193Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,612,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M193I) has been classified as Uncertain significance.
Frequency
Consequence
NM_002230.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JUP | NM_002230.4 | c.578T>C | p.Met193Thr | missense_variant | 4/14 | ENST00000393931.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JUP | ENST00000393931.8 | c.578T>C | p.Met193Thr | missense_variant | 4/14 | 1 | NM_002230.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000724 AC: 18AN: 248456Hom.: 0 AF XY: 0.0000669 AC XY: 9AN XY: 134616
GnomAD4 exome AF: 0.000183 AC: 267AN: 1460578Hom.: 0 Cov.: 33 AF XY: 0.000173 AC XY: 126AN XY: 726596
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74344
ClinVar
Submissions by phenotype
Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 193 of the JUP protein (p.Met193Thr). This variant is present in population databases (rs139496777, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257, 31983221). ClinVar contains an entry for this variant (Variation ID: 222661). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 12, 2021 | - - |
Wolff-Parkinson-White pattern Uncertain:1
Uncertain significance, no assertion criteria provided | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Jul 14, 2017 | This variant was identified in an individual with Wolff-Parkinson-White syndrome - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2020 | Identified in an individual with DCM in the published literature (Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 222661; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31983221, 27532257) - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 15, 2015 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 07, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at